Children conceived using assisted reproductive technology, including in vitro fertilization, may be at risk for premature cardiovascular disease, a small study found.

Compared with controls, healthy children born after the use of assisted reproductive technology had significantly smaller average flow-mediated dilation of the brachial artery (6.7% versus 8.6%, P<0.0001), reported Urs Scherrer, MD, from University Hospital in Bern, Switzerland, and colleagues.

The children conceived with reproductive assistance also had significantly faster mean carotid-femoral pulse-wave velocity (7.8 versus 6.5 m/s, P<0.001) and greater average carotid intima-media thickness (410 versus 370 µm, P<0.0001), according to the study published April 17 in Circulation: Journal of the American Heart Association.

Scherrer and colleagues examined many different variables and concluded that the actual process of embryo manipulation was the likely cause of the vascular dysfunction, which also was seen in the pulmonary vasculature.

"What might cause these putative epigenetic changes in ART [assisted reproductive technology] embryos?" asked David S. Celermajer, MB, PhD, DSc, from the University of Sydney in Australia, in an accompanying editorial.

Celermajer suggested that "parental subfertility" could be the result of epigenetic changes, which then are passed on to the offspring who manifest them with "different phenotypic consequences."

These changes also could result from the handling of the embryos, exposure outside the body, or exposure to chemical-rich culture media, he said.

Although Scherrer and colleagues noted a similar systemic vascular dysfunction in children with type 1 diabetes, Celermajer said it is too early to "screen or treat such children and young adults differently."

However, Celermajer called for more studies examining the effects of gamete and embryo manipulation, as well as studies examining the long-term health in children conceived using assisted reproductive technology.

Although such technology has been used for about three decades, there is little data on the long-term health concerns of children born from these methods. Of course, the lack of data could be due to the fact that "clinically manifest disease may not yet have had time to develop," Scherrer and colleagues said.

To determine whether these children exhibited any subclinical cardiovascular dysfunction, researchers recruited 65 healthy Swiss children (mean age 12) conceived by assisted reproductive technology. They also enrolled 57 control children born during the same period.

Among the children conceived using assisted reproductive technology, 21 were conceived by in vitro fertilization and 44 by intracytoplasmic sperm injection. Fresh embryos were transferred immediately in 48 cases; in the remaining 17, zygotes were kept frozen to be transferred later.

Researchers found many baseline similarities between the controls and the children conceived with reproductive assistance, including arterial blood pressure; body mass index; levels of lipids, glucose, and insulin; and birth weight, which has been theorized as a possible reason for vascular dysfunction later in life.

The two groups also had similar maternal characteristics such as gestational age, body mass index, smoking status, and cardiovascular risk profile.

Echocardiography revealed no structural heart damage in either group of children.

Along with the differences in brachial and carotid arterial function, the children conceived with reproductive assistance also had pulmonary vascular dysfunction. For example, children conceived with reproductive assistance had a 30% higher mean systolic pulmonary artery pressure (39 versus 30 mm Hg, P<0.0001).

Arterial oxygen saturation and the cardiac index were similar in both groups.

Also similar were the mean diameter of the inferior vena cava and its respiratory change, and the left atrial pressure.

To the researchers, this signified that the higher systolic pressure in the children conceived with assisted reproductive technology was due to pulmonary vascular dysfunction and not cardiac dysfunction.

There were no systemic and pulmonary differences between children conceived with the help of in vitro fertilization and those born after intracytoplasmic sperm injection. Nor were there differences between children of mothers whose embryos were transferred immediately or those whose mothers had their embryos frozen for a later transfer.

Several other analyses were conducted, which included looking for arterial differences related to children born to sterile and fertile parents or related to children conceived naturally after hormonal stimulation of ovulation. Researchers said that none of these factors played a role in vascular dysfunction.

In fact, multivariate analysis pegged assisted reproductive technology as an independent predictor of all vascular parameters.

"Collectively, these observations provide no evidence that parent-related factors play an important role and suggest that vascular dysfunction in offspring of assisted reproductive technology is related to the procedure itself," researchers wrote.

Despite the small study sample, Celermajer said the study has several strengths, including the various analyses between children born with reproductive assistance and controls, as well as between the various techniques and between the sterile and fertile parents.

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